Pharmacology-II

Course code PMS-616

By Dr. Junaid Athar Khattak

ANTI-BIOTICS
Cell Wall Synthesis Inhibitors

4th Semester

Institute of paramedical sciences,

Khyber Medical University Peshawar
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CONTENTS
Penicillins
Cephalosporins

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 Introduction to Anti Biotics
Definitions:
• Antimicrobial drugs: Drugs that are used to treat infections with micro-organisms are
known as antimicrobial drugs.
• Antibiotics: Antibiotics are chemical substances produced from various microorganisms
(bacteria and fungi) that kill or inhibit the growth of other microorganisms.
• Bacteriostatic: when a chemical substance inhibit bacterial growth and proliferation
• Bactericidal: when a chemical substance kill bacteria
• Antibiotic resistance: Antibiotic resistance is the ability of bacteria/fungi to resist the
effects of an antibiotic.
• Narrow spectrum antibiotics: are active against a selected group of bacterial types. They
can act on either gram +ve or gram –ve but not both. Narrow spectrum antibiotics are used
for the specific infection when the causative organism is known
• Broad-spectrum antibiotics: are a class of antibiotics that act against an extensive range of
disease-causing bacteria by targeting both gram-positive and gram-negative bacterial
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groups.
 Introduction to Anti Biotics (Definitions)
• Minimum inhibitory concentration (MIC): It is the lowest concentration of a chemical which
prevents visible growth of a bacterium
• Infection: the invasion and multiplication of pathogenic microorganisms in body tissues,
causing disease by local cellular injury, secretion of a toxin or by antigen–antibody reaction in
the host.
• Sepsis: The presence of bacteria (bacteremia), other infectious organisms, or toxins created by
infectious organisms in the bloodstream with spread throughout the body. It is a potentially
life-threatening complication of an infection. Sepsis occurs when chemicals released into the
bloodstream to fight the infection trigger inflammatory responses throughout the body damage
multiple organ systems.
• Bacteremia or Septicemia: is the presence of viable bacteria in the circulating blood.
• Super infection: a new infection occurring in a patient having a preexisting infection; for
example, bacterial infection may occur in patients with viral respiratory disease.
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Diagrammatic view of bacteriostatic, bactericidal, and
resistance in antibiotics

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 Antimicrobial drugs

Common microbes causing diseases

• Bacteria......anti bacterial / Anti biotic (Topic of our interest)

• Viruses……anti viral
• Fungi………anti fungal
• Protozoa ……antiprotozoal

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 History of antibiotics
• Before penicillin introduction, there was no effective treatment for infections.
In 1928, penicillin, the first true antibiotic, was discovered by Alexander
Fleming, Professor of Bacteriology at St. Mary's Hospital in London.
• Alexander Fleming was a bit disorderly in his work. He left one of his
petridishe uncovered. Upon returning from holidays, he noticed that a
fungus, Penicillium notatum, had contaminated a culture plate
of Staphylococcus bacteria.
• The fungus had created bacteria-free zones wherever it grew on the plate.
Fleming isolated and grew the mould in pure culture. He found that P.
notatum proved extremely effective even at very low concentrations,
preventing Staphylococcus growth even when diluted 800 times.
• Fleming published his findings in the British Journal of Experimental
Pathology in June 1929. 8
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 Classification of antibacterial drugs

1. Bacterial cell wall synthesis Inhibitors…. ( Examples… Penicillins, Cephalosporins,

Carbapenems, Monobactams)

2. Bacterial protein synthesis Inhibitors…. ( Examples… Tetracyclines,

Aminoglycosides, Macrolides, Chloramphenicol, Linezolid)

3. Bacterial DNA synthesis Inhibitors…. ( Examples… Quinolones, and Sulfonamides)

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 Cell wall synthesis inhibitors
• This group consist of such antibiotic classes which will inhibit bacterial cell wall
synthesis.
• The important two classes of this group are Penicillins and Cephalosporins.
• All penicillin's and cephalosporins have beta lactam ring (6-amino-penicillanic
acid), therefore they are called beta lactam antibiotics.
• Apart from Penicillins and cephalosporins, we have beta lactamase inhibitors,
which are also having beta lactam ring, for example
o Clavulanic Acid
o Sulbactam
o Tazobactam

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Penicillin and Cephalosporin structures

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 PENECILLINS
• Penicillins are antibiotics derived from several strains of common moulds.

• Penicillins are the 1st ever antibiotics to be discovered

• Derived from Penicillium Notatum (Fungi)

• Then up to 20-30 years, there was no antibiotic except penicillin.

• These are β-Lactam antibiotics

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 PENECILLINS CLASSIFICATION
 Two major groups c) Penicillinase resistant penicillin
A) Natural Penicillins  Methicillin
 Penicillin G (Benzyl penicillin)  Nafcillin
 Penicillin V (Oral)  Oxacillin
 Benzathine penicillin  Cloxacillin
B) Semisynthetic Penicillins  Dicloxacillin
a) Long-acting penicillin d) Extended spectrum penicillin
 Procaine penicillin  Ampicillin
b) Orally effective Penicillin  Amoxicillin
 Propicillin 14
 Mechanism of action of penicillin
The synthesis of cell wall of bacteria is completely depended upon an enzyme
named as transpeptidase (Penicillin binding proteins (PBPs)). This enzyme cross-
links peptidoglycan chains to form rigid cell walls. Penicillins inhibits the cell wall
of bacteria by irreversibly blocking transpeptidase action. (Enough)

NOTE:
A critical part of the process is the recognition of the D-Ala-D-Ala sequence of the
NAMA peptide side chain by the PBP. Interfering with this recognition disrupts the
cell wall synthesis.
β-lactams mimic the structure of the D-Ala-D-Ala link and bind to the active
site of PBPs, disrupting the cross-linking process.
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 Peptidoglycan
Peptidoglycan is polymer of sugars and amino acids. The sugar part is composed of alternating
units of N-acetylmuramic acid (NAMA) and N-acetylglucosamine (NAGA).These alternating
sugars are connected by a glycosidic bond. A peptide chain (amino acids) is attached to the
NAMA which is crossed linked to amino acids chain on a neighboring NAMA unit.

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 Therapeutic uses of penicillin
o Initially used for respiratory infections o Typhoid
o Tetanus
 Pneumonia
o Rheumatoid arthritis
 Pharyngitis o Anthrax
 Bronchitis o Syphilis
o Meningitis
 Sinusitis
o Gonorrhea

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 Adverse effects of penicillin
o Allergic reactions o On Blood
Cause sever allergic reactions  Blood Dyskinesias
particularly with IV injections, may be Thrombocytopenia
anaphylactic shock leading to death.
Heamolytic anemia
So initially test dose is given
subcutaneously. o On GIT
o Skin  Nausea
 Urticaria Vomiting
 Skin rashes Diarrhea
o Cation toxicity o Hepatitis
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 CONTRA INDICATIOS
o Contra indicated in patients which are allergic to cephalosporin.
o Patients having hepatic and renal failure.

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 Resistance development to penicillin
o β-Lactamase activity:
 Bacteria produces some enzymes (β-Lactamase ) against penicillin to break down
the drug, which diminishes its activity.
o Decreased permeability to the drug:
 Bacteria brings changes in its cell wall to affect the permeability / penetration of
the drug inside the cell.
 secondly the presence of an efflux drug can also decrease the amount of intra
cellular drug
o Alteration in PBP (Transpeptidase):
Bacteria modifies its penicillin binding protein. Modified PBPs have a20lower
Inactivation of penicillin

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Anti biotic susceptibility/Resistance test

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 Introduction to Cephalosporin
o Cephalosporin drugs are beta lactam antibiotics that inhibit the cell wall of
bacteria.
o Cephalosporin C was first isolated from a fungus named as Cephalosporium
acremonium by Dr. Abraham in 1948.
o These are bactericidal antibiotics as they kill the micro-organisms when used at
therapeutic dose.
Mode of Action: As penicillin
 Cell wall synthesis inhibitors.

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 Mechanism of action of cephalosporins
The synthesis of cell wall of bacteria is completely depended upon an enzyme
named as transpeptidase (Cephalosporin binding proteins (CBPs)). This enzyme
cross-links peptidoglycan chains to form rigid cell walls. Cephalosporin inhibits
the cell wall of bacteria by irreversibly blocking transpeptidase action. (Enough)

NOTE:
A critical part of the process is the recognition of the D-Ala-D-Ala sequence of
the NAMA peptide side chain by the CBP. Interfering with this recognition
disrupts the cell wall synthesis.
β-lactams mimic the structure of the D-Ala-D-Ala link and bind to the active
site of PBPs, disrupting the cross-linking process. 24
 CEPHALOSPORINS CLASSIFICATION
o Total 4 different generations/groups 2). 2nd generation cephalosporin
1). 1st generation cephalosporin A). Oral 2nd generation cephalosporin
A). Oral 1st generation cephalosporin  Cefaclor
 Cephalexin B). Parenteral 2nd generation
 Cephradine cephalosporin
 Cephadroxil  Cefamandole
B). Parenteral 1st generation  Cefonicid
cephalosporin
 Cephazoline
 Cephalothine
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 CEPHALOSPORINS CLASSIFICATION
3). 3rd generation cephalosporin 2). 4th generation cephalosporin
A). Oral 3rd generation cephalosporin  Cefepime
 Cefixime  Cefpirome
 Cefpodoxime
B). Parenteral 3rd generation
cephalosporin
 Cefotaxime
 Ceftriaxone
 Cefoperazone
 Ceftazidime
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 CEPHALOSPORINS CLASSIFICATION
• First Generation: The optimum activity of all first generation cephalosporin
drugs is against Gram-positive bacteria such as staphylococci and streptococci.
• The second generation drugs have more activity against Gram-negative bacteria
(Haemophilus influenzae, Enterobacter aerogenes) in comparison to the first
generation. Their Gram positive spectrum is less than the first generation.
• Third generation cephalosporin drugs are broad spectrum and the effective
against both Gram positive and gram negative bacteria.
• Fourth generation cephalosporin: These are extended spectrum antibiotics.
They are resistant to beta lactamases.

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 Clinical indications of cephalosporins
1). 1st generation cephalosporin 2). 2nd generation cephalosporin
( Can't cross BBBs) A). Oral 2nd generation cephalosporin
A). Oral 1st generation cephalosporin  Sinusitis
 UTI’s  Otitis media
 Cellulitis  Lower respiratory tract infections
 Soft tissue abscess B). Parenteral 2nd generation
B). Parenteral 1st generation cephalosporin
cephalosporin  Peritonitis
 Surgical prophylaxis  Pneumonia
 As an alternative to penicillin allergic
patients
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 CEPHALOSPORINS CLASSIFICATION
3). 3rd generation cephalosporin 2). 4th generation cephalosporin
 Meningitis  Meningitis
 Sepsis  Sepsis
 Gonorrhea  Gonorrhea

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 Adverse effects of Cephalosporins
o Allergic reactions o On Blood
Thrombocytopenia
 Less than Penicillins because the
o On GIT
extant of population allergy is less than
 Nausea
penicillin. Vomiting
Anaphylaxis Diarrhea
o Kidney
 Skin rashes
 Intestinal Nephritis
Drug fever
 Renal tubular necrosis
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 Adverse effects of Cephalosporins
o Local irritation and pain at the site of IM injection.
o Local thrombophlebitis (Thrombi formation) at the site of IV injection.

CONTRA INDICATIOS
 Contra indicated in patients which are allergic to cephalosporin.

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 Resistance development to Cephalosporin
o β-Lactamase activity:
 Bacteria produces some enzymes (β-Lactamase ) against cephalosporin to break down the
drug, which diminishes its activity.
They are not susceptible to hydrolysis by staphylococcal penicillinase.
o Decreased permeability to the drug:
 Bacteria brings changes in its cell wall to affect the permeability / penetration of the drug
inside the cell.
 secondly the presence of an efflux drug can also decrease the amount of intra cellular drug
o Alteration in CBP (Transpeptidase):
Bacteria modifies its cephalosporin binding protein. Modified CBPs have a lower affinity
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Any Question?
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